GIAPREZA
Angiotensin II Vasopressor for Septic and Distributive Shock
Quick Facts About GIAPREZA
Key Takeaways About GIAPREZA
- ICU-only emergency vasopressor: GIAPREZA is used exclusively in intensive care for adults with septic or distributive shock unresponsive to standard vasopressor therapy
- Unique mechanism of action: Unlike catecholamine vasopressors, GIAPREZA acts through the renin-angiotensin-aldosterone system (RAAS), providing an alternative pathway to raise blood pressure
- Blood clot risk: Thromboembolic events (blood clots) are a significant risk; prophylactic anticoagulation should be administered concurrently
- Continuous monitoring required: Blood pressure must be closely monitored throughout treatment, with dose titration every 5 minutes as needed
- Gradual discontinuation: GIAPREZA must be tapered gradually when the underlying condition improves; abrupt discontinuation can cause dangerous blood pressure drops
What Is GIAPREZA and What Is It Used For?
GIAPREZA (angiotensin II) is a vasopressor medication administered by continuous intravenous infusion in hospital intensive care units. It is used to increase blood pressure in adults with septic or other distributive shock who remain critically hypotensive despite adequate fluid resuscitation and treatment with first-line vasopressors.
GIAPREZA contains a synthetic form of angiotensin II, a peptide hormone that the human body naturally produces as part of the renin-angiotensin-aldosterone system (RAAS). Under normal physiological conditions, angiotensin II plays a central role in regulating blood pressure and fluid balance. When blood pressure or blood volume falls, the kidneys release renin, which triggers a cascade that ultimately produces angiotensin II. This hormone then acts on specific receptors (AT1 receptors) in blood vessel walls, causing them to constrict and thereby increasing blood pressure.
In septic shock, the body's normal regulatory mechanisms are overwhelmed by a severe systemic inflammatory response to infection. Blood vessels dilate profoundly, and blood pressure drops to dangerously low levels – a condition known as distributive shock. When this hypotension does not respond to intravenous fluids and standard catecholamine vasopressors such as norepinephrine (the recommended first-line agent according to the Surviving Sepsis Campaign), additional vasopressor support is needed. This is where GIAPREZA fills a critical therapeutic gap.
The pivotal ATHOS-3 trial (Angiotensin II for the Treatment of High-Output Shock), published in the New England Journal of Medicine in 2017, demonstrated that angiotensin II significantly improved blood pressure in patients with vasodilatory shock who were not responding to high doses of conventional vasopressors. In this randomised, double-blind, placebo-controlled trial, 69.9% of patients receiving angiotensin II achieved the target blood pressure response at 3 hours, compared with only 23.4% in the placebo group.
It is important to understand that GIAPREZA is not a first-line treatment for shock. Current international guidelines, including the Surviving Sepsis Campaign (SSC) 2021 recommendations and the European Society of Intensive Care Medicine (ESICM) guidelines, recommend norepinephrine as the first-choice vasopressor for septic shock, followed by vasopressin as a second-line agent. GIAPREZA is positioned as an adjunctive vasopressor when these agents alone are insufficient to maintain adequate blood pressure and organ perfusion.
GIAPREZA was approved by the United States Food and Drug Administration (FDA) in December 2017 and received European Medicines Agency (EMA) authorisation for use within the EU. It represents the first new class of vasopressor to become available for the treatment of shock in decades, offering an alternative mechanism of action through the RAAS pathway rather than the adrenergic pathway used by catecholamine-based vasopressors.
What Should You Know Before Receiving GIAPREZA?
Before receiving GIAPREZA, your intensive care team must be informed of any history of blood clots, allergy to angiotensin II, and all other medications you are currently receiving. GIAPREZA is contraindicated only in patients with known hypersensitivity to angiotensin II or any excipient, but several important warnings apply.
Contraindications
You should not receive GIAPREZA if any of the following apply:
- Known allergy to angiotensin II or to any of the other ingredients in GIAPREZA (mannitol, sodium hydroxide, hydrochloric acid, water for injections) – symptoms of an allergic reaction may include skin rash, itching, swelling of the face or throat, or difficulty breathing
Although the contraindications are limited, several serious warnings and precautions must be carefully considered before and during treatment.
Warnings and Precautions
GIAPREZA carries significant risks that require close medical monitoring. Your intensive care team should be aware of the following:
GIAPREZA has been associated with an increased incidence of arterial and venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE). In clinical trials, thromboembolic events occurred more frequently in patients receiving GIAPREZA than in those receiving placebo. As a precaution, concurrent venous thromboembolism (VTE) prophylaxis should be administered to all patients receiving GIAPREZA, unless contraindicated. Alert your medical team immediately if you notice any colour changes (redness or pallor), pain, numbness in your arms or legs, or if your extremities feel cold to the touch – these may be signs that a blood clot has obstructed blood flow to a part of the body.
GIAPREZA has been evaluated only in patients with septic and distributive shock. It has not been studied in other types of shock, such as cardiogenic, hypovolaemic, or obstructive shock, and its safety and efficacy in those settings are unknown.
When GIAPREZA treatment is first initiated, an increase in blood pressure is expected. Patients will be continuously monitored using invasive arterial blood pressure measurement to ensure the blood pressure remains within a safe and appropriate range. Your target mean arterial pressure (MAP) will typically be set at 65–75 mmHg, consistent with international critical care guidelines.
Elderly Patients
GIAPREZA has been tested in a limited number of patients over 75 years of age. No specific dose adjustments are required based on age alone. However, elderly patients are more likely to have pre-existing cardiovascular conditions and reduced organ function, which may alter their response to the medication. Your intensive care physician will continuously monitor your blood pressure and adjust the infusion rate based on your individual haemodynamic response.
Liver and Kidney Impairment
No dose adjustments are required for patients with impaired liver or kidney function. Angiotensin II is primarily metabolised by endogenous aminopeptidases and angiotensin-converting enzyme 2 (ACE2), rather than by hepatic or renal pathways. Nevertheless, your intensive care team will closely monitor your organ function and blood pressure response throughout treatment and will adjust the dose accordingly.
Children and Adolescents
GIAPREZA should not be used in children and adolescents under 18 years of age. The safety and effectiveness of angiotensin II have not been studied in paediatric populations. Treatment of paediatric septic shock follows distinct guidelines, and alternative vasopressor agents with established paediatric evidence should be used. Healthcare professionals managing paediatric septic shock should refer to the American College of Critical Care Medicine (ACCM) guidelines for paediatric haemodynamic support.
Pregnancy and Breastfeeding
There is limited information on the effects of GIAPREZA during pregnancy. Given that GIAPREZA acts on the renin-angiotensin system – and other drugs affecting this system (ACE inhibitors, ARBs) are known to cause foetal harm – the use of GIAPREZA during pregnancy should be avoided whenever possible. You will only receive this medication if your treating physician determines that the potential benefit to your life outweighs the potential risks to the developing foetus.
It is not known whether angiotensin II passes into breast milk. Given the critical clinical context in which GIAPREZA is used (life-threatening septic shock), breastfeeding considerations are typically secondary. However, your medical team should be informed if you are breastfeeding, and a decision will be made balancing the benefits of treatment against any potential risk to the infant.
The effects of GIAPREZA on human fertility are unknown. No dedicated fertility studies have been conducted.
Sodium Content
GIAPREZA contains less than 1 mmol sodium (23 mg) per vial and is therefore considered essentially sodium-free. This is relevant for patients on sodium-restricted diets, although in the clinical context of septic shock, dietary sodium considerations are typically not a primary concern.
How Does GIAPREZA Interact with Other Drugs?
GIAPREZA can interact with ACE inhibitors (which may enhance its effects) and angiotensin receptor blockers (which may reduce its effects). Because GIAPREZA is used in critically ill patients who are typically receiving multiple medications simultaneously, careful haemodynamic monitoring is essential throughout treatment.
Angiotensin II has a very short plasma half-life of less than one minute, and it is metabolised by endogenous aminopeptidases rather than by the cytochrome P450 enzyme system. This means that many of the drug–drug interactions that affect other medications (those metabolised by CYP enzymes) are not directly applicable to GIAPREZA. However, several pharmacodynamic interactions are clinically important, particularly with other agents that affect the renin-angiotensin-aldosterone system.
Clinically Important Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| ACE inhibitors (e.g. enalapril, ramipril, lisinopril) | Antihypertensive | ACE inhibitors block the breakdown of angiotensin II, potentially increasing its vasopressor effect and leading to excessive blood pressure elevation | Monitor blood pressure closely; may require lower GIAPREZA starting dose |
| ARBs (e.g. losartan, valsartan, candesartan) | Antihypertensive | ARBs block angiotensin II type 1 (AT1) receptors, directly opposing the mechanism of action of GIAPREZA and reducing its vasopressor effect | Higher GIAPREZA doses may be required; monitor haemodynamic response carefully |
| Other vasopressors (norepinephrine, vasopressin, phenylephrine) | Vasopressor / vasoactive agents | Additive vasoconstrictive effects leading to excessive blood pressure elevation or end-organ ischaemia | Dose reduction of concomitant vasopressors may be needed once GIAPREZA effect is established |
| Anticoagulants (heparin, enoxaparin) | Thromboprophylaxis | No direct pharmacokinetic interaction; however, VTE prophylaxis is strongly recommended due to the thromboembolic risk of GIAPREZA | Concurrent use is recommended rather than a concern; ensure VTE prophylaxis is administered |
Because GIAPREZA is invariably used alongside other vasoactive agents in the ICU, careful dose titration and continuous haemodynamic monitoring are essential. When GIAPREZA is added to an existing vasopressor regimen, your intensive care team may need to reduce the doses of the other vasopressors to prevent excessive vasoconstriction. This is standard practice in multimodal vasopressor therapy and ensures a balanced approach to blood pressure support.
Unlike many oral medications, GIAPREZA does not interact with food or beverages, as it is administered exclusively by intravenous infusion in the ICU setting. There are no relevant interactions with herbal supplements or over-the-counter medications in the context of its clinical use.
What Is the Correct Dosage of GIAPREZA?
GIAPREZA is administered by continuous intravenous infusion. The recommended starting dose is 20 nanograms per kilogram per minute (ng/kg/min). The dose is titrated every 5 minutes, up to a maximum of 80 ng/kg/min during the first 3 hours, then maintained at no more than 40 ng/kg/min thereafter.
GIAPREZA must be prescribed by a physician experienced in the management of shock and must be administered exclusively in an intensive care setting with continuous haemodynamic monitoring. The drug is supplied as a concentrated solution (2.5 mg/mL) that must be diluted before use.
Preparation and Dilution
Dilution Instructions
Inspect each vial for particulate matter before dilution. Dilute 1 mL or 2 mL of GIAPREZA concentrate in 0.9% sodium chloride (normal saline) to achieve a final concentration of 5,000 ng/mL or 10,000 ng/mL. The diluted solution should be clear and colourless. Discard the vial and any unused solution after use.
Stability: The diluted solution should be used immediately. If not used immediately, it may be stored for up to 24 hours at room temperature or at 2–8°C (refrigerated).
Adults
Septic and Distributive Shock
Starting dose: 20 ng/kg/min by continuous intravenous infusion
Titration: Increase in increments of up to 15 ng/kg/min every 5 minutes as needed to achieve the target mean arterial pressure (MAP), typically 65–75 mmHg
Maximum dose (first 3 hours): 80 ng/kg/min
Maximum maintenance dose (after 3 hours): 40 ng/kg/min
Minimum dose: Doses as low as 1.25 ng/kg/min may be used during tapering
Approximately one in four patients in clinical trials experienced transient hypertension at the starting dose of 20 ng/kg/min and required down-titration.
Special Populations
| Patient Group | Dose Adjustment | Notes |
|---|---|---|
| Elderly (over 75 years) | No specific adjustment required | Monitor blood pressure closely; titrate based on individual response |
| Hepatic impairment | No dose adjustment required | Angiotensin II is not hepatically metabolised via CYP enzymes |
| Renal impairment | No dose adjustment required | Monitor kidney function as part of standard ICU care |
| Children (<18 years) | Not recommended | Safety and efficacy not established in paediatric populations |
Duration of Treatment
In clinical trials, the median duration of GIAPREZA treatment was 48 hours, with a range of 3.5 to 168 hours (up to 7 days). Treatment duration is entirely dependent on the patient's clinical status. GIAPREZA should be administered at the lowest effective dose for the shortest duration necessary to maintain adequate arterial blood pressure and tissue perfusion.
Overdose
Because GIAPREZA is administered by medical professionals in a closely monitored ICU environment, accidental overdose is unlikely. However, if excessive doses are given, the primary expected effect is hypertension (excessively high blood pressure). In the event of overdose, your healthcare team will immediately reduce or stop the infusion, monitor your vital signs continuously, and provide supportive care as needed. The very short half-life of angiotensin II (less than one minute) means that the haemodynamic effects will diminish rapidly once the infusion is reduced or discontinued.
Stopping Treatment
When your blood pressure has stabilised sufficiently and the underlying cause of shock is improving, your intensive care team will gradually taper the GIAPREZA infusion rather than stopping it abruptly. The dose is reduced in decrements of up to 15 ng/kg/min, guided by your blood pressure response. Abrupt discontinuation may lead to rebound hypotension (a sudden and dangerous drop in blood pressure) or a deterioration of your clinical condition.
What Are the Side Effects of GIAPREZA?
Like all medicines, GIAPREZA can cause side effects. The most significant risk is thromboembolic events (blood clots), which can occur in more than 1 in 10 patients. Hypertension (excessively high blood pressure) is also very common and requires careful dose titration. Tachycardia and peripheral ischaemia are common side effects.
The side effect profile of GIAPREZA must be interpreted in the context of its clinical use – critically ill patients in intensive care who already have a high burden of disease. Many of the adverse events observed in clinical trials may be related to the underlying condition (sepsis, multiorgan failure) rather than to the drug itself. Nevertheless, certain adverse effects are directly attributable to the pharmacological action of angiotensin II.
Tell your doctor or nurse immediately if you experience pain, redness, pale colour, swelling, or coldness when touching the skin of your arms or legs. These may be symptoms of a blood clot (thromboembolic event) that has blocked blood flow. Blood clots can travel from the veins to the lungs (pulmonary embolism), causing chest pain and breathing difficulties. Although not all thromboembolic symptoms lead to life-threatening complications, your medical team must be informed immediately.
Very Common
- Thromboembolic events – blood clots forming in arteries or veins, including deep vein thrombosis (DVT) and pulmonary embolism (PE); this is the most significant safety concern
- Hypertension – blood pressure rising above the target range, particularly at the start of treatment or at higher doses; requires dose reduction
Common
- Tachycardia – rapid heart rate, which may be a reflexive response to vasoconstriction or related to the underlying septic state
- Peripheral ischaemia – poor blood circulation to the hands, feet, or other body areas due to excessive vasoconstriction; in severe cases this can cause tissue damage (ischaemic necrosis)
Uncommon to Rare
- Metabolic acidosis – build-up of acid in the blood, potentially related to reduced tissue perfusion in critically ill patients
- Hyperglycaemia – elevated blood sugar levels, a known effect of RAAS activation
- Delirium or altered mental status – common in ICU patients and potentially multifactorial
It is important to note that in the clinical trial setting (ATHOS-3), the overall 28-day mortality rate was numerically lower in the GIAPREZA group (46%) compared with placebo (54%), although this difference did not reach statistical significance. The Day 7 survival rate was also improved in the angiotensin II group, suggesting that the benefits of effective blood pressure restoration in refractory shock may outweigh the thromboembolic risks when appropriate prophylactic measures are in place.
Healthcare professionals and patients are encouraged to report suspected adverse reactions to their national pharmacovigilance authority. In the UK, reports can be made via the Yellow Card Scheme. In the US, adverse events can be reported to the FDA MedWatch program. In the EU, reports should be submitted through the respective national competent authority. Reporting helps regulatory agencies continuously monitor the benefit-risk balance of medicines.
How Should You Store GIAPREZA?
GIAPREZA concentrate must be stored in a refrigerator at 2–8°C. The diluted solution should be used immediately, but may be stored for up to 24 hours at room temperature or refrigerated. Do not use if the solution is discoloured or contains visible particles.
GIAPREZA is a hospital-only medication that is stored and handled by pharmacy and nursing staff. Patients will not typically need to handle or store this medication themselves. However, the following storage information is provided for completeness and for the benefit of healthcare professionals:
- Unopened vials: Store in a refrigerator at 2–8°C. Keep the vials in the outer carton to protect from light.
- Diluted solution: Use immediately after preparation. If not used immediately, the diluted solution remains chemically and physically stable for up to 24 hours at room temperature or at 2–8°C.
- Expiry date: Do not use GIAPREZA after the expiry date printed on the carton and vial label (after “EXP”). The expiry date refers to the last day of the stated month.
- Visual inspection: Do not use the medication if you observe visible damage, discolouration, or particulate matter in the solution. The solution should be clear and colourless.
- Keep out of reach of children.
- Disposal: Any unused product or waste material should be disposed of in accordance with local hospital guidelines for pharmaceutical waste.
What Does GIAPREZA Contain?
GIAPREZA contains angiotensin II acetate as the active ingredient, equivalent to 2.5 mg of angiotensin II per millilitre. Inactive ingredients include mannitol and water for injections, with pH adjusted using sodium hydroxide and hydrochloric acid.
Active Ingredient
The active substance in GIAPREZA is angiotensin II acetate. Each millilitre of concentrate contains angiotensin II acetate equivalent to 2.5 mg of angiotensin II. GIAPREZA is available in two vial sizes:
- 1 mL vial: Contains 2.5 mg angiotensin II
- 2 mL vial: Contains 5 mg angiotensin II
Inactive Ingredients (Excipients)
- Mannitol – a sugar alcohol used as an excipient for osmolality adjustment and stabilisation
- Water for injections – the solvent vehicle
- Sodium hydroxide and/or hydrochloric acid – used for pH adjustment to ensure compatibility with intravenous administration
Appearance and Packaging
GIAPREZA is supplied as a concentrate for solution for infusion (sterile concentrate). The solution is a clear, colourless liquid without visible particles. It is packaged in single-use glass vials. Available pack sizes include 1 × 1 mL, 10 × 1 mL, and 1 × 2 mL vials. Not all pack sizes may be marketed in every country.
The marketing authorisation holder is PAION Deutschland GmbH, Heussstraße 25, 52078 Aachen, Germany. The manufacturer is PAION Netherlands B.V., Vogt 21, 6422 RK Heerlen, Netherlands.
Frequently Asked Questions About GIAPREZA
GIAPREZA (angiotensin II) is an emergency vasopressor medication used in intensive care units to raise dangerously low blood pressure in adults with septic or other distributive shock. It is reserved for patients who do not respond adequately to standard treatments including intravenous fluids and first-line vasopressors such as norepinephrine. GIAPREZA works by mimicking the body's natural angiotensin II hormone, which causes blood vessels to constrict and thereby increases blood pressure.
While both GIAPREZA and norepinephrine are vasopressors that raise blood pressure, they work through entirely different mechanisms. Norepinephrine acts on adrenergic (alpha-1) receptors, whereas GIAPREZA acts on angiotensin II type 1 (AT1) receptors in the renin-angiotensin-aldosterone system. This makes GIAPREZA particularly valuable in patients with catecholamine-resistant shock, where the adrenergic pathway has become desensitised. GIAPREZA is typically used as an add-on therapy rather than a replacement for norepinephrine.
The most significant risk associated with GIAPREZA is the increased incidence of thromboembolic events – blood clots that can form in arteries or veins. These include deep vein thrombosis and potentially life-threatening pulmonary embolism. To mitigate this risk, concurrent blood-thinning medication (VTE prophylaxis) is recommended during GIAPREZA treatment. Excessively high blood pressure (hypertension) is also a very common side effect that requires careful dose monitoring and adjustment.
No, GIAPREZA is not approved for use in children or adolescents under 18 years of age. The safety and efficacy of angiotensin II have not been studied in paediatric populations. Children with septic shock are managed according to separate paediatric guidelines using other vasopressors that have established evidence in younger age groups. Healthcare teams treating paediatric septic shock should consult paediatric critical care specialists.
The duration of GIAPREZA treatment varies depending on the individual patient's clinical response and recovery. In the pivotal clinical trial (ATHOS-3), the median treatment duration was 48 hours, with patients receiving the drug for anywhere between 3.5 hours and 7 days. GIAPREZA should be discontinued as soon as the underlying shock has improved sufficiently, with the dose gradually tapered to prevent rebound drops in blood pressure.
The primary evidence for GIAPREZA comes from the ATHOS-3 trial, a multicentre, randomised, double-blind, placebo-controlled study published in the New England Journal of Medicine in 2017. The trial enrolled 344 patients with vasodilatory shock and demonstrated that angiotensin II significantly improved blood pressure compared with placebo, with a 69.9% response rate versus 23.4% in the placebo group at 3 hours. Subsequent analyses have also suggested potential benefits for patients with acute kidney injury requiring renal replacement therapy.
References
- Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. New England Journal of Medicine. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154
- Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Medicine. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y
- European Medicines Agency (EMA). GIAPREZA – Summary of Product Characteristics. Available at: https://www.ema.europa.eu/
- U.S. Food and Drug Administration (FDA). GIAPREZA Prescribing Information. Approved December 2017. Available at: https://www.accessdata.fda.gov/
- Tumlin JA, Murugan R, Deane AM, et al. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Critical Care Medicine. 2018;46(6):949-957. doi:10.1097/CCM.0000000000003092
- Wunderink RG, Albertson TE, Engoren M, et al. Angiotensin II for Catecholamine-Refractory Vasodilatory Shock – A Subgroup Analysis of the ATHOS-3 Trial. Journal of Critical Care. 2020;57:231-237.
- Bellomo R, Forni LG, Busse LW, et al. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. American Journal of Respiratory and Critical Care Medicine. 2020;202(9):1253-1261. doi:10.1164/rccm.201911-2172OC
- World Health Organization (WHO). Sepsis Fact Sheet. Available at: https://www.who.int/news-room/fact-sheets/detail/sepsis
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Medicine. 2017;43(3):304-377. doi:10.1007/s00134-017-4683-6
- Vincent JL, De Backer D. Circulatory Shock. New England Journal of Medicine. 2013;369(18):1726-1734. doi:10.1056/NEJMra1208943
About Our Medical Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, comprising licensed specialist physicians in critical care medicine, anaesthesiology, and clinical pharmacology. Our editorial process follows the GRADE evidence framework to ensure all information is based on the highest quality evidence available.
All medical claims in this article are supported by peer-reviewed research published in journals indexed in PubMed and the Cochrane Library. We prioritise Level 1A evidence (systematic reviews and meta-analyses of randomised controlled trials) and follow international guidelines from the Surviving Sepsis Campaign, SCCM, ESICM, and WHO.
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